ABSTRACT Mastectomy is performed on approximately half of women with breast cancer. Postmastectomy breast reconstruction has benefits for body image, sexuality, self-esteem, and quality of life. Poor clinical prognoses after breast reconstruction often involve mastectomy skin flap necrosis (MSFN) or other complications associated with the lack of blood flow and oxygenation to wound tissue volumes. MSFN and wound dehiscence leads to a number of challenges, including wound management problems, delays to adjuvant therapy, esthetic compromise, implant extrusion, patient distress, and financial loss. A technology that allows surgeons to perioperatively assess and optimize preservation of skin flaps while avoiding complications is essential to ensure successful clinical outcomes. Although alternative techniques have been explored to identify ischemic-hypoxic tissues at risk of necrosis, none have achieved universal acceptance as each technique has a few challenging issues that decrease its clinical usefulness. Moreover, no single technique provides both blood flow and oxygenation information, which are essential for precise assessment of skin flap viability. Our recent innovative development of near-infrared speckle contrast diffuse correlation tomography (scDCT) technique provides a noninvasive (dye-free) and noncontact means for continuous 2D/3D imaging of blood flow distributions throughout large/thick tissue volumes such as mastectomy skin flaps. We propose to extend this scDCT prototype to a next generation multi-wavelength scDCT (MW-scDCT) device for perioperative imaging of both blood flow and oxygenation distributions in mastectomy skin flaps. New high-speed algorithms for 2D mapping and 3D image reconstruction will be developed to accommodate rapid online assessment of skin flap hemodynamics. This MW-scDCT system will be tested/optimized using standard tissue-simulating phantoms (Aim 1) and calibrated/validated against a commercial dye-based fluorescence angiography device (SPY Elite) in swine (Aim 2) and patients (Aim 3) undergoing mastectomy with expander-implant based breast reconstruction. The in vivo studies will determine the capability of our MW-scDCT for intraoperative prediction of MSFN regions/volumes and postoperative optimization of incremental expander volumes to reduce risks of MSFN and other complications. We expect that combined measurements of preoperative baseline and intraoperative alteration in skin flap flow and oxygenation will provide a more accurate assessment of skin flap viability than a one-time single-parameter measurement (i.e., blood flow, blood oxygenation, or fluorescence perfusion). Study outcomes will provide the rationale for designing MW-scDCT guided clinical trials of mastectomy with breast reconstruction to reduce postoperative complications and healthcare costs. Moreover, this noninvasive (dye-free), noncontact, continuous, and cost-efficient imaging system has the potential for perioperative use in many other clinical settings, especially where contact measurements may not be possible, such as for continual and longitudinal monitoring of burns, wounds, and other types of tissue flaps.